Grin2a Hypofunction Disrupts Hippocampal Network Oscillations and E/I Balance Contributing to Cognitive Deficits

BackgroundN-methyl-D-aspartate (NMDA) receptors, particularly those containing the GluN2A subunit, play a critical role in hippocampal-dependent learning and memory. The GluN2A subunit, encoded by the Grin2a gene, is essential for maintaining cognitive function, including working memory. In this study, we explore how Grin2a mutations impair working memory and disrupt hippocampal network oscillations and E/I balance. MethodsGrin2a mutant mice were assessed for spatial working memory deficits using the 8-arm radial maze. We utilized multi-electrode arrays and whole-cell patch-clamp electrophysiology to evaluate network oscillation and synaptic inputs to pyramidal cells in ex vivo hippocampal slices. We performed an immunohistochemical analysis of hippocampal slices to evaluate changes in the abundance of GABAergic neurons. ResultsOur results demonstrate that Grin2a deficiency impairs spatial working memory and disrupts coupling of theta-gamma oscillations in the hippocampus. Moreover, Grin2a mutants express an overabundance of parvalbumin-expressing (PV+) interneurons that integrate into hippocampal circuits and destabilize excitatory/inhibitory (E/I) input to CA1 pyramidal neurons. ConclusionThis study highlights the critical role of GluN2A-containing NMDA receptors in maintaining hippocampal network synchrony. Impairments in network synchrony and E/I balance within the hippocampus may drive the cognitive deficits observed in Grin2a-related disorders such as schizophrenia, epilepsy, and intellectual disability.